Abstract
Pathogenic SNF2 related chromatin remodeling ATPase 1 (SMARCA1) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel SMARCA1 variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous SMARCA1 variant (NM_003069.5:c.1795 C > T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G > T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between SMARCA1 and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing SMARCA1 function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.
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Acknowledgements
We thank the participants for their cooperation. We also thank Ms. K. Takabe, Mr. T. Miyama, Ms. N. Watanabe, Ms. M. Sato, and Ms. S. Sugimoto at the Department of Human Genetics, Yokohama City University Graduate School of Medicine, Japan for their technical assistance. We thank Rachel James, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
Funding
This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant numbers JP24ek0109674, JP24ek0109760, JP24ek0109617, JP24ek0109648, and JP24ek0109677 (N. Matsumoto); Japan Society for the Promotion of Science (JSPS) KAKENHI under grant numbers JP23K27568 and JP23K18278 (T. Mizuguchi), JP24K18862 (M. Sakamoto), JP23K07229 (Y. Uchiyama), JP23K15353 (N. Tsuchida), JP21K07869 (E. Koshimizu), JP23K27520 (S. Miyatake), and JP24K02230 (N. Matsumoto); and the Takeda Science Foundation (T. Mizuguchi, N. Matsumoto).
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Nishimura, N., Mizuguchi, T., Hamada, K. et al. Hemizygous SMARCA1 variants cause X-linked intellectual disability. J Hum Genet 70, 359–363 (2025). https://doi.org/10.1038/s10038-025-01346-w
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DOI: https://doi.org/10.1038/s10038-025-01346-w
